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Objective To evaluate the evidence addressing the association between the use of ovarian stimulation drugs and the risk of breast cancer. Design Systematic review and meta-analysis. Setting Not applicable. Patient(s) Women without any previous history of breast cancer undergoing ovarian stimulation. Intervention(s) Electronic databases were searched from 1990 until January 2020. All cohort studies reporting new incidences of breast cancer in infertile women using ovarian stimulating drugs were included. Treated (exposed) infertile women were compared with the unexposed general population with unexposed infertile women as controls. Main Outcome Measure(s) New diagnosis of breast cancer within an infertile and general population after exposure to ovarian stimulation drugs. Result(s) Overall, the quality of evidence was very low because of the serious risk of bias and indirectness (nonrandomized studies). There was no significant increase in the risk of breast cancer among women treated with any ovarian stimulation drug for infertility compared with that in unexposed controls from the general population and the infertile population (pooled odds ratio 1.03, 95% Confidence interval 0.86 to 1.23, 20 studies, I2 = 88.41%, very low quality of evidence). Furthermore, no significant increase in the risk of breast cancer was found with the use of clomiphene citrate or gonadotropins, alone or in combination. Conclusion(s) The current study found that the use of clomiphene citrate and gonadotropins in infertile women was not associated with an increased risk of breast cancer.

It is known that lifestyle factors affect sporadic miscarriage, but the extent of this on RPL (recurrent pregnancy loss) is less well known. A systematic review and meta-analysis was performed to assess the associations between lifestyle factors and RPL. Studies that analysed RPL in the context of BMI, smoking, alcohol and caffeine intake were included. The primary and secondary outcomes were odds of having RPL in the general population and odds of further miscarriage, respectively. Underweight and women with BMI > 25 are at higher odds of RPL in the general population (OR 1.2, 95% CI 1.12–1.28 and OR 1.21, 95% CI 1.06–1.38, respectively). In women with RPL, having BMI > 30 and BMI > 25 has increased odds of further miscarriages (OR 1.77, 95% CI 1.25–2.50 and OR 1.35, 95% CI 1.07–1.72, respectively). The quality of the evidence for our findings was low or very low. Being underweight and BMI > 25 contributes significantly to increased risk of RPL (general population). BMI > 25 or BMI > 30 increases the risk of further miscarriages (RPL population). Larger studies addressing the effects of alcohol, cigarette smoking and caffeine on the risk of RPL with optimisation of BMI in this cohort of women are now needed.

STUDY QUESTION Does endometriosis affect live birth following donor oocyte recipient versus autologous IVF? SUMMARY ANSWER There was no significant difference in the live birth rate (LBR) in women with endometriosis undergoing donor oocyte recipient cycles versus autologous IVF cycles. WHAT IS KNOWN ALREADY For infertile women with endometriosis, IVF is often considered as a treatment option. Lower implantation and pregnancy rates have been observed following IVF in women with endometriosis. It has been debated whether the lower pregnancy rate is due to the effect on oocyte quality or the endometrium, thus affecting implantation. To delineate whether endometriosis affects oocyte quality or the endometrium, we planned a study, using a donor oocyte recipient model, where the recipients were women diagnosed with endometriosis and compared their outcomes with women who underwent autologous IVF, who had also been diagnosed with endometriosis. STUDY DESIGN, SIZE, DURATION Human Fertilization and Embryology Authority (HFEA) anonymized data from 1996 to 2016 were analyzed. This comprised of a total of 758 donor oocyte recipients, where the recipients were women diagnosed with endometriosis, and 12 856 autologous IVF cycles where the women were diagnosed with endometriosis as the sole cause of infertility. PARTICIPANTS/MATERIALS, SETTING, METHODS Data on all women with endometriosis undergoing donor oocyte recipient and autologous IVF cycles were analyzed to compare live birth outcomes. Logistic regression analysis was performed adjusting for number of previous IVF cycles, previous live birth, period of treatment, day of embryo transfer, number of embryos transferred and fresh or frozen embryo transfer cycle. MAIN RESULTS AND THE ROLE OF CHANCE There was no significant difference in the LBR in women with endometriosis undergoing donor oocyte recipient fresh embryo transfer cycles compared to women undergoing autologous IVF fresh embryo transfer cycles (31.6% vs 31.0%; odds ratio (OR) 1.03, 99.5% CI 0.79–1.35). After adjusting for confounders, there was no significant difference in LBR in women with endometriosis undergoing donor oocyte recipient fresh embryo transfer cycles versus autologous fresh embryo transfer cycles (adjusted OR (aOR) 1.05, 99.5% CI 0.79–1.41). There was no significant difference in the LBR in women with endometriosis undergoing donor oocyte recipient frozen embryo transfer cycles compared to women undergoing autologous frozen embryo transfer cycles (19.6% vs 24.0%; OR 0.77, 99.5% CI 0.47–1.25). After adjusting for potential confounders, there was no significant difference in the LBR in women undergoing donor oocyte recipient frozen embryo transfer cycles compared with autologous frozen embryo transfer cycles (aOR 0.85, 99.5% CI 0.51–1.41). LIMITATIONS, REASONS FOR CAUTION Although the analysis was adjusted for potential confounders, there was no information on the extent and classification of endometriosis as well as oocyte number. Furthermore, adenomyosis is thought to co-exist in women with endometriosis and may have independent pathophysiological mechanisms affecting fertility, for which there was no information. WIDER IMPLICATIONS OF THE FINDINGS The study shows no difference in LBR between donor oocyte recipient cycles in which all recipients had endometriosis compared to autologous IVF cycles in women with endometriosis. Therefore, this study finding suggests that there may be a minimal or no effect of oocyte quality on IVF outcomes in women with endometriosis. STUDY FUNDING/COMPETING INTEREST(S) No funding was obtained. M.S.K. is an associate editor with Human Reproduction Open. He was not involved in the editorial or peer review process for the manuscript. TRIAL REGISTRATION NUMBER N/A.

Objective To evaluate the risk of monozygotic splitting with embryo biopsy during in vitro fertilisation (IVF). Design A cohort study. Setting Anonymised assisted reproductive technology national data from the Human Fertilisation and Embryology Authority, UK. Population Women undergoing single-embryo transfer (SET) following either pre-implantation genetic testing (PGT) involving embryo biopsy or IVF without PGT. Methods Data on women undergoing SET either following PGT and non-PGT IVF treatment in 2000-2016 were analysed to compare the risk of zygotic splitting and monozygotic twining. Logistic regression analysis was performed adjusting for potential confounders. Main outcomes Monozygotic spitting, monozygotic twin birth. Results Data comprising a total of 207 697 SET cycles (4544 following PGT and 203 153 following non-PGT IVF) were analysed. The live birth rate per embryo transfer was 31.9% (95% confidence interval [CI] 30.5-33.2%) following PGT and 26.9% (95% CI 26.7-27.1%) following non-PGT IVF. The incidence of zygotic splitting following PGT was 2.4% (95% CI 1.7-3.3%) versus 1.5% (95% CI 1.4-1.6%) following non-PGT IVF. There was a significantly higher risk of zygotic splitting with PGT versus non-PGT IVF cycles (odds ratio [OR] 1.64, 95% CI 1.19-2.27). The higher risk of zygotic splitting with PGT cycles remained significant after adjusting for potential confounders (adjusted OR 1.51, 95% CI 1.06-2.15). Conclusions The present study demonstrated an increased risk of monozygotic splitting with embryo biopsy. Given the current sparse literature, it is important to accumulate further evidence to validate the findings. Tweetable abstract A likely increased risk of monozygotic splitting following embryo biopsy.

It is essential that fertility treatment is individualized based on a thorough diagnostic work-up, with treatment tailored to the patients' requirements. This individualization should be kept in mind during the main decision points that occur before and during treatment. Treatment customization must include consideration of both the woman and her partner involved in the process together, including their collective treatment goals. Once treatment goals have been agreed and diagnostic evaluations performed, personalization based on patient characteristics, together with an understanding of treatment goals and patient preferences, enables the selection of appropriate treatments, protocols, products and their dosing. Following treatment initiation, monitoring and adaptation of product and dose can then ensure optimal outcomes. Currently, it is not possible to base treatment decisions on every characteristic of the patient and personalization is based on biomarkers that have been identified as the most relevant. However, in the future, the use of artificial intelligence coupled with continuous monitoring should enable greater individualization and improve outcomes. This review considers the current state-of-the-art related to decision points during individualized treatment of female infertility, before looking at future developments that might further assist in making individualized treatment decisions, including the use of computer-assisted decision making. ispartof: GYNECOLOGICAL ENDOCRINOLOGY vol:35 issue:12 pages:1027-1036 ispartof: location:England status: published

Study question Does endometriosis affect live birth following donor oocyte recipient versus autologous in vitro fertilisation (IVF) cycle. Summary answer There was no significant difference in the live birth rate (LBR) in women with endometriosis undergoing donor oocyte recipient versus autologous IVF cycle. What is known already For infertile women with endometriosis, IVF is often considered as a treatment option. Lower implantation and pregnancy rates have been observed following IVF in women with endometriosis when compared to tubal factor infertility. It has been debated that lower pregnancy rates following IVF in endometriosis is due to both oocyte quality and the endometrium. To delineate whether endometriosis affects oocyte quality or the endometrium, we planned a study using donor oocyte recipient model where the recipient were women with endometriosis. We compared the LBR after oocyte recipient cycle with autologous IVF in women with endometriosis Study design, size, duration We obtained anonymised dataset of all the IVF cycles performed in the UK since 19991 from the Human Fertilization and Embryology Authority (HFEA). Data from 1996 to 2016 comprising a total of 13 627 donor oocyte recipient and autologous IVF cycles with endometriosis and no other cause of infertility were analysed. Participants/materials, setting, methods Data on all women with endometriosis undergoing fresh or frozen IVF treatment cycles were analysed to compare the LBR between donor oocyte recipient and autologous treatment cycles. Logistic regression analysis was performed adjusting for number of previous IVF cycles, previous live birth, period of treatment, day of embryo transfer, number of embryo transferred, fresh and frozen cycle. Main results and the role of chance There was no significant difference in the LBR in women with endometriosis undergoing donor oocyte recipient fresh cycles compared to women undergoing fresh autologous IVF cycles (31.6% vs. 31.0%; odds ratio, OR 1.03, 99% CI 0.79 – 1.35). After adjusting for confounders listed above, there was no significant difference in LBR in women undergoing donor oocyte recipient fresh cycles versus fresh autologous ART cycles (aOR 1.06, 99% CI 0.79 – 1.42). There was no significant difference in the LBR in women with endometriosis undergoing frozen donor oocyte recipient cycles compared to women undergoing autologous frozen embryo transfer cycles (19.6% vs. 24.0%; OR 0.77, 99% CI 0.47 - 1.25). After adjusting for potential confounders, there was no significant difference in the LBR in women undergoing frozen donor oocyte recipient cycles compared with autologous frozen embryo transfer cycles (aOR 0.84, 99% CI 0.50 - 1.41). Limitations, reasons for caution Although the analysis was adjusted for several potential confounders, there was no information on classification of endometriosis to allow adjustment. Wider implications of the findings The current study design does not indicate endometriosis has an impact on oocyte quality given that the outcomes in donor oocyte recipient cycles are comparable with autologous IVF cycles. These findings need to be further studied and validated. Trial registration number Not applicable

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To evaluate the effectiveness and safety of artificial oocyte activation in women with infertility undergoing intracytoplasmic sperm injection treatment.

Time taken to achieve a live birth is an important consideration that is central to managing patient expectations during infertility treatment. However, time-related endpoints are not reported as standard in the majority of fertility-related clinical studies and there is no internationally recognized consensus definition for such endpoints. There is, therefore, a need for meaningful discussions around the selection of appropriate time-related treatment outcome measures for studies evaluating fertility treatments that will be relevant to diverse stakeholders (e.g. patients, healthcare professionals, clinical scientists, authorities and industry). Here, we provide a proposal for the evaluation of time-related outcome measures in fertility-related clinical studies, alongside associated definitions. ispartof: HUMAN REPRODUCTION vol:35 issue:8 pages:1732-1739 ispartof: location:England status: published

STUDY QUESTION Does the cause of infertility affect the perinatal outcomes preterm birth (PTB) and low birth weight (LBW) following IVF treatment? SUMMARY ANSWER The risk of PTB and LBW was higher with female causes of infertility—ovulatory disorders, tubal disorders and endometriosis—compared to unexplained infertility but the absolute increase in risk was low. WHAT IS KNOWN ALREADY Infertility is associated with an increased risk of adverse perinatal outcomes. Risk of adverse perinatal outcomes is also higher following ART compared to spontaneous conceptions. Infertility can result from female and/or male factors or is unexplained when the cause cannot be delineated by standard investigations. Given that infertility and ART are contributory to the adverse perinatal outcomes, it is a matter of interest to delineate if the specific cause of infertility influences perinatal outcomes following IVF treatment. STUDY DESIGN, SIZE, DURATION Anonymous data were obtained from the Human Fertilization and Embryology Authority (HFEA). The HFEA has collected data prospectively on all ART cycles performed in the UK since 1991. Data from 1991 to 2016 comprising a total of 117 401 singleton live births following IVF with or without ICSI (IVF ± ICSI) for sole causes of infertility were analysed for PTB and LBW. Cycles having more than one cause of infertility and/or multiple births were excluded. PARTICIPANTS/MATERIALS, SETTING, METHODS Data on all women undergoing stimulated IVF ± ICSI treatment cycles were analysed to compare perinatal outcomes of PTB and LBW among singleton live births based on the cause of infertility (ovulatory disorders, tubal disorders, endometriosis, male factor, unexplained). Logistic regression analysis was performed, adjusting for female age category, period of treatment, previous live births, IVF or ICSI, number of embryos transferred and fresh or frozen embryo transfer cycles. MAIN RESULTS AND THE ROLE OF CHANCE Compared to unexplained infertility, the risk of PTB was significantly higher with ovulatory disorders (adjusted odds ratio (aOR) 1.31, 99.5% CI 1.17 to 1.46); tubal disorders (aOR 1.25, 99.5% CI 1.14 to 1.38) and endometriosis (aOR 1.17, 99.5% CI 1.01 to 1.35). There was no significant difference in the risk of PTB with male factor causes compared to unexplained infertility (aOR 1.01, 99.5% CI 0.93, 1.10). The risk of LBW was significantly higher with ovulatory disorders (aOR 1. 29, 99.5% CI 1.16 to 1.44) and tubal disorders (aOR 1.12, 99.5% CI 1.02 to 1.23) and there was no increase in the risk of LBW with endometriosis (aOR 1.11, 99.5% CI 0.96 to 1.30) and male factor causes (aOR 0.94, 99.5% CI 0.87, 1.03), compared to unexplained infertility. LIMITATIONS, REASONS FOR CAUTION Although the analysis was adjusted for several important confounders, there was no information on the medical history of women during pregnancy to allow adjustment. The limitations with observational data would apply to this study, including residual confounding. WIDER IMPLICATIONS OF THE FINDINGS This is the largest study to address the causes of infertility affecting perinatal outcomes of PTB and LBW. The information is important for the management of pregnancies and the underlying reasons for the associations observed need to be further understood. STUDY FUNDING/COMPETING INTEREST(S) No funding was obtained. There are no competing interests to declare. TRIAL REGISTRATION NUMBER N/A.

The prolonged lockdown of health services providing high-complexity fertility treatments –as currently recommended by many reproductive medicine entities– is detrimental for society as a whole, and infertility patients in particular. Globally, approximately 0.3% of all infants born every year are conceived using assisted reproductive technology (ART) treatments. By contrast, the total number of COVID-19 deaths reported so far represents approximately 1.0% of the total deaths expected to occur worldwide over the first three months of the current year. It seems, therefore, that the number of infants expected to be conceived and born –but who will not be so due to the lockdown of infertility services– might be as significant as the total number of deaths attributed to the COVID-19 pandemic. We herein propose remedies that include a prognostic-stratification of more vulnerable infertility cases in order to plan a progressive restart of worldwide fertility treatments. At a time when preventing complications and limiting burdens for national health systems represent relevant issues, our viewpoint might help competent authorities and health care providers to identify patients who should be prioritized for the continuation of fertility care in a safe environment.

Research Question How much the variability in patients’ response during in vitro fertilization (IVF) may add to the initial predicted prognosis based only on patients’ basal characteristics? Design Anonymous data were obtained from the Human Fertilization and Embryology Authority (HFEA). Data involving 114,882 stimulated fresh IVF cycles were retrospectively analyzed. Logistic regression was used to develop the models. Results Prediction of live birth was feasible with moderate accuracy in all of the three models; discrimination of the model based only on basal patients’ characteristics (AUROC 0.61) was markedly improved adding information of number of embryos (AUROC 0.65) and, mostly, number of oocytes (AUROC 0.66). Conclusions The addition to prediction models of parameters such as the number of embryos obtained and especially the number of oocytes retrieved can statistically significantly improve the overall prediction of live birth probabilities when based on only basal patients’ characteristics. This seems to be particularly true for women after the first IVF cycle. Since ovarian response affects the probability of live birth in IVF, it is highly recommended to add markers of ovarian response to models based on basal characteristics to increase their predictive ability.

Study question Does transfer of multiple embryos affect perinatal outcomes of resulting singleton live births following ART? Summary answer There is a higher risk of preterm birth (PTB) and low birthweight (LBW) in singleton live births associated with spontaneous reduction of an initial multiple to singleton gestation following transfer of multiple embryos. What is known already Singleton pregnancies following ART are at a higher risk of adverse perinatal outcomes compared to spontaneous conceptions. Earlier studies have found an increased risk of PTB and LBW in singletons following transfer of multiple embryos versus single embryo transfer (SET). However, these studies did not address the specific role of vanishing twin, i.e. spontaneous reduction of an initial multiple to singleton gestation. Study design, size, duration Anonymised data on all ART cycles performed in the UK were obtained from the Human Fertilization and Embryology Authority. Data from 1991 to 2011 involving 508 410 fresh and 131 157 frozen autologous ART cycles resulting in 95 779 and 18 005 singleton live births, respectively, were analyzed. Participants/materials, setting, methods Fresh and frozen ART cycles were analyzed separately to compare perinatal outcomes of PTB and LBW of singleton live births resulting from transfer of multiple (≥2) embryos versus SET. Logistic regression analysis was performed adjusting for confounders. Subgroup analyses were carried out for perinatal outcomes of singleton live births with initial multiple or initial single gestational sacs following transfer of multiple embryos versus singleton live births following SET. Main results and the role of chance In fresh cycles, there was a significantly higher risk of PTB (adjusted odds ratio (aOR) 2.70, CI 2.37-3.05) and LBW (aOR 2.76, CI 2.44-3.13) in singleton live births with initial multiple gestational sacs but there was no significant difference in the risk of PTB (aOR 1.08, CI 1.00-1.16) or LBW (aOR 1.08, CI 1.00-1.16) in singleton live births with an initial single gestational sac following transfer of ≥2 embryos compared to those following SET. In frozen cycles, there was a significantly higher risk of PTB (aOR 2.13, CI: 1.55-2.93) and LBW (aOR 2.61, CI: 1.87-3.64) in singleton live births with initial multiple gestational sacs but there was no significant difference in the risk of PTB (aOR 1.02, CI: 0.88-1.18) or LBW (aOR 0.91, CI: 0.77-1.07) in the singleton live births with an initial single gestational sac following transfer of ≥2 embryos compared to those following SET. Limitations, reasons for caution While the analysis was adjusted for a number of known confounders, the dataset had no information for confounders such as smoking, BMI, previous obstetric history and comorbid medical conditions during pregnancy. The lack of information about the timing of occurrence of the vanishing phenomenon is another limitation because poorer perinatal outcomes of a surviving twin have been reported following second trimester fetal demise compared to the first trimester. Wider implications of the findings The study results suggest that the vanishing twin phenomenon is associated with increased risk of PTB and LBW in the resulting singleton live births and there was no increased risk when there was a single gestational sac from the outset following transfer of multiple embryos. Study funding/competing interests Nil.

Although most medical treatments are designed for the average patient with a one-size-fits-all-approach, they may not benefit all. Better understanding of the function of genes, proteins, and metabolite, and of personal and environmental factors has led to a call for personalized medicine. Personalized reproductive medicine is still in its infancy, without clear guidance on treatment aspects that could be personalized and on trial design to evaluate personalized treatment effect and benefit-harm balance. While the rationale for a personalized approach often relies on retrospective analyses of large observational studies or real-world data, solid evidence of superiority of a personalized approach will come from randomized trials comparing outcomes and safety between a personalized and one-size-fits-all strategy. A more efficient, targeted randomized trial design may recruit only patients or couples for which the personalized approach would differ from the previous, standard approach. Multiple monocenter studies using the same study protocol (allowing future meta-analysis) might reduce the major center effect associated with multicenter studies. In certain cases, single-arm observational studies can generate the necessary evidence for a personalized approach. This review describes each of the main segments of patient care in assisted reproductive technologies treatment, addressing which aspects could be personalized, emphasizing current evidence and relevant study design. ispartof: FERTILITY AND STERILITY vol:109 issue:6 pages:968-979 ispartof: location:United States status: published

Pregnancies resulting from assisted reproductive techniques are at higher risk of adverse perinatal outcomes compared with spontaneous conceptions. Underlying infertility and IVF procedures have been linked to adverse perinatal outcomes. It is important to know if ovarian stimulation influences perinatal outcomes after IVF. A systematic search for relevant studies was conducted up to November 2016 on the following databases: PubMed, EMBASE, DARE and Cochrane Central Register of Controlled Trials. Perinatal outcomes included preterm birth (PTB), low birth weight (LBW), small for gestational age (SGA), large for gestational age (LGA) and congenital anomalies. Data from four studies, which included a total of 96,996 and 704 singleton live births after stimulated IVF and natural or modified natural cycle IVF, were included in the meta-analysis. The risk of PTB (RR 1.27, 95% CI 1.03 to 1.58) and LBW (RR 1.95, 95% CI 1.03 to 3.67) were significantly higher after stimulated compared with natural or modified natural cycle IVF. Data from one study were available for SGA, LGA, congenital anomalies and no significant differences were reported between the groups. This study suggests a higher risk of PTB and LBW after stimulated IVF compared with natural or modified natural IVF, although the absolute increase in risk may be low.

A higher risk of pregnancy complications occurs after assisted reproductive techniques compared with spontaneously conceived pregnancies. This is attributed to the underlying infertility and assisted reproduction technique procedures involved during treatment. It is a matter of interest whether use of donor oocytes affects perinatal outcomes compared with pregnancies after autologous IVF. Anonymized data were obtained from the Human Fertilization and Embryology Authority. The analysis included 5929 oocyte donation and 127,856 autologous IVF live births. Data from all women who underwent donor oocyte recipient or autologous IVF cycles, both followed with fresh embryo transfer, were analysed to compare perinatal outcomes of preterm birth (PTB) and low birthweight (LBW) after singleton and multiple live births. The risk of adverse perinatal outcomes after oocyte donation was increased: adjusted OR (aOR) 1.56, 99.5% CI 1.34 to 1.80 for PTB and aOR 1.43, 99.5% CI 1.24 to 1.66 for LBW were significantly higher after oocyte donation compared with autologous IVF singletons. The adjusted odds PTB (aOR 1.21, 99.5% CI 1.02 to 1.43) was significantly higher after oocyte donation compared with autologous IVF multiple births. Analysis of this large dataset suggests significantly higher risk of PTB and LBW after ooctye donation compared with autologous IVF pregnancies.

[This corrects the article DOI: 10.1093/hropen/hoaa009.][This corrects the article DOI: 10.1093/hropen/hoaa009.].

STUDY QUESTIONAre systematic reviews published within a 3-year period on interventions in ART concordant in their conclusions?SUMMARY ANSWERThe majority of the systematic reviews published within a 3-year period in the field of assisted reproduction on the same topic had discordant conclusions.WHAT IS KNOWN ALREADYSystematic reviews and meta-analyses have now replaced individual randomized controlled trials (RCTs) at the top of the evidence pyramid. There has been a proliferation of systematic reviews and meta-analyses, many of which suffer from methodological issues and provide varying conclusions.STUDY DESIGN, SIZE, DURATIONWe assessed nine interventions in women undergoing ART with at least three systematic reviews each, published from January 2015 to December 2017.PARTICIPANTS/MATERIALS, SETTING, METHODSThe systematic reviews which included RCTs were considered eligible for inclusion. The primary outcome was extent of concordance between systematic reviews on the same topic. Secondary outcomes included assessment of quality of systematic reviews, differences in included studies in meta-analyses covering the same search period, selective reporting and reporting the quality of evidence.MAIN RESULTS AND THE ROLE OF CHANCEConcordant results and conclusions were found in only one topic, with reviews in the remaining eight topics displaying partial discordance. The AMSTAR grading for the majority of the non-Cochrane reviews was critically low whilst it was categorized as high for all of the Cochrane reviews. For three of the nine topics, none of the included systematic reviews assessed the quality of evidence. We were unable to assess selective reporting as most of the reviews did not have a pre-specified published protocol.LIMITATIONS, REASONS FOR CAUTIONWe were limited by the high proportion of reviews lacking a pre-specified protocol, which made it impossible to assess for selective reporting. Furthermore, many reviews did not specify primary and secondary outcomes which made it difficult to assess reporting bias. All the authors of this review were Cochrane review authors which may introduce some assessment bias. The categorization of the review’s conclusions as beneficial, harmful or neutral was subjective, depending on the tone and wording of the conclusion section of the review.WIDER IMPLICATIONS OF THE FINDINGSThe majority of the systematic reviews published within a 3-year period on the same topic in the field of assisted reproduction revealed discordant conclusions and suffered from serious methodological issues, hindering the process of informed healthcare decision-making.STUDY FUNDING/COMPETING INTEREST(S)All the authors are Cochrane authors. M.S.K. is an editorial board member of Cochrane Gynaecology and Fertility group. No grant from funding agencies in the public, commercial or not-for-profit sectors was obtained.

The first commercially available gonadotropin product was a human chorionic gonadotropin (hCG) extract, followed by animal pituitary gonadotropin extracts. These extracts were effective, leading to the introduction of the two-step protocol, which involved ovarian stimulation using animal gonadotropins followed by ovulation triggering using hCG. However, ovarian response to animal gonadotropins was maintained for only a short period of time due to immune recognition. This prompted the development of human pituitary gonadotropins; however, supply problems, the risk for Creutzfeld-Jakob disease, and the advent of recombinant technology eventually led to the withdrawal of human pituitary gonadotropin from the market. Urinary human menopausal gonadotropin (hMG) preparations were also produced, with subsequent improvements in purification techniques enabling development of products with standardized proportions of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) activity. In 1962 the first reported pregnancy following ovulation stimulation with hMG and ovulation induction with hCG was described, and this product was later established as part of the standard protocol for ART. Improvements in immunopurification techniques enabled the removal of LH from hMG preparations; however, unidentified urinary protein contaminants remained a problem. Subsequently, monoclonal FSH antibodies were used to produce a highly purified FSH preparation containing

Objectives: To investigate whether live birth (LB) is associated with oocyte yield and number of biopsied and suitable blastocyst to transfer following preimplantation genetic testing (PGT) for monogenic disorders (PGT-M) and chromosomal structural rearrangements (PGT-SR). Study design: All couples underwent controlled ovarian stimulation, blastocyst biopsy, vitrification and transfer of suitable embryo(s) in a frozen embryo transfer (FET) cycle. Results: Of 175 couples who underwent PGT treatment, 249 oocytes retrievals were carried out and 230 FET were subsequently undertaken. 122/230 (53%, 95% CI 47–59) FET resulted in a LB and 16/230 (7%, 95% CI 4–11) have resulted in ongoing pregnancies. 21/230 (9%, 95% CI 6–14) FET resulted in miscarriage and 69/230 (30%, 95% CI 24–36) concluded with failed implantation. Two (1%, 95% CI 0–3) transfers underwent termination for congenital malformation, with no evidence of misdiagnosis by prenatal testing. The relationship between number of oocytes retrieved and number of blastocysts biopsied and suitable embryos to transfer were significant (p = 0.00; Incidence rate ratio (IRR) 1.05; 95% 1.04–1.06; p = 0.00; IRR 1.04; 95%, 1.03–1.06), respectively. The number of oocytes collected (p = 0.007; OR 1.06; 95% CI 1.01–1.10), the number of blastocysts biopsied (p = 0.001; OR 1.14; 95% 95% CI 1.06–1.23) and the number of suitable embryos to transfer (p = 0.00; OR 1.38; 95% CI 1.17–1.64) were all significantly associated with the odds of achieving a LB. There is a 14% and 38% increased chance of a LB per additional blastocyst biopsied and suitable embryo to transfer, respectively. Conclusions: PGT-M and PGT-SR outcomes are significantly associated with egg yield, number of blastocysts to biopsy and suitable embryos to transfer. Keywords: Live birth, Preimplantation genetic testing, Monogenic disorders, Chromosomal rearrangements, Oocyte, Blastocysts

BACKGROUND: Screening hysteroscopy in infertile women with unexplained infertility, or prior to intrauterine insemination (IUI) or in vitro fertilisation (IVF) may reveal intrauterine pathology that may not be detected by routine transvaginal ultrasound. Hysteroscopy, whether purely diagnostic or operative may improve reproductive outcomes. OBJECTIVES: To assess the effectiveness and safety of screening hysteroscopy in subfertile women undergoing evaluation for infertility, and subfertile women undergoing IUI or IVF. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL CRSO, MEDLINE, Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform (September 2018). We searched reference lists of relevant articles and handsearched relevant conference proceedings. SELECTION CRITERIA: Randomised controlled trials comparing screening hysteroscopy versus no intervention in subfertile women wishing to conceive spontaneously, or before undergoing IUI or IVF. DATA COLLECTION AND ANALYSIS: We independently screened studies, extracted data, and assessed the risk of bias. The primary outcomes were live birth rate and complications following hysteroscopy. We analysed data using risk ratio (RR) and a fixed-effect model. We assessed the quality of the evidence by using GRADE criteria. MAIN RESULTS: We retrieved 11 studies. We included one trial that evaluated screening hysteroscopy versus no hysteroscopy, in women with unexplained subfertility, who were trying to conceive spontaneously. We are uncertain whether ongoing pregnancy rate improves following a screening hysteroscopy in women with at least two years of unexplained subfertility (RR 4.30, 95% CI 2.29 to 8.07; 1 RCT; participants = 200; very low-quality evidence). For a typical clinic with a 10% ongoing pregnancy rate without hysteroscopy, performing a screening hysteroscopy would be expected to result in ongoing pregnancy rates between 23% and 81%. The included study reported no adverse events in either treatment arm. We are uncertain whether clinical pregnancy rate is improved (RR 3.80, 95% CI 2.31 to 6.24; 1 RCT; participants = 200; very low-quality evidence), or miscarriage rate increases (RR 2.80, 95% CI 1.05 to 7.48; 1 RCT; participants = 200; very low-quality evidence), following screening hysteroscopy in women with at least two years of unexplained subfertility.We included ten trials that included 1836 women who had a screening hysteroscopy and 1914 women who had no hysteroscopy prior to IVF. Main limitations in the quality of evidence were inadequate reporting of study methods and higher statistical heterogeneity. Eight of the ten trials had unclear risk of bias for allocation concealment.Performing a screening hysteroscopy before IVF may increase live birth rate (RR 1.26, 95% CI 1.11 to 1.43; 6 RCTs; participants = 2745; I² = 69 %; low-quality evidence). For a typical clinic with a 22% live birth rate, performing a screening hysteroscopy would be expected to result in live birth rates between 25% and 32%. However, sensitivity analysis done by pooling results from trials at low risk of bias showed no increase in live birth rate following a screening hysteroscopy (RR 0.99, 95% CI 0.82 to 1.18; 2 RCTs; participants = 1452; I² = 0%).Only four trials reported complications following hysteroscopy; of these, three trials recorded no events in either group. We are uncertain whether a screening hysteroscopy is associated with higher adverse events (Peto odds ratio 7.47, 95% CI 0.15 to 376.42; 4 RCTs; participants = 1872; I² = not applicable; very low-quality evidence).Performing a screening hysteroscopy before IVF may increase clinical pregnancy rate (RR 1.32, 95% CI 1.20 to 1.45; 10 RCTs; participants = 3750; I² = 49%; low-quality evidence). For a typical clinic with a 28% clinical pregnancy rate, performing a screening hysteroscopy would be expected to result in clinical pregnancy rates between 33% and 40%.There may be little or no difference in miscarriage rate following screening hysteroscopy (RR 1.01, 95% CI 0.67 to 1.50; 3 RCTs; participants = 1669; I² = 0%; low-quality evidence).We found no trials that compared a screening hysteroscopy versus no hysteroscopy before IUI. AUTHORS' CONCLUSIONS: At present, there is no high-quality evidence to support the routine use of hysteroscopy as a screening tool in the general population of subfertile women with a normal ultrasound or hysterosalpingogram in the basic fertility work-up for improving reproductive success rates.In women undergoing IVF, low-quality evidence, including all of the studies reporting these outcomes, suggests that performing a screening hysteroscopy before IVF may increase live birth and clinical pregnancy rates. However, pooled results from the only two trials with a low risk of bias did not show a benefit of screening hysteroscopy before IVF.Since the studies showing an effect are those with unclear allocation concealment, we are uncertain whether a routine screening hysteroscopy increases live birth and clinical pregnancy, be it for all women, or those with two or more failed IVF attempts. There is insufficient data to draw conclusions about the safety of screening hysteroscopy. ispartof: COCHRANE DATABASE OF SYSTEMATIC REVIEWS vol:4 issue:4 ispartof: location:England status: published

A growing list of clinical adjuncts are being used during in vitro fertilization (IVF) treatment. Most of these IVF add-ons (such as growth hormone, aspirin, heparin, dehydroepiandrostenedione, testosterone, male and female antioxidants, and screening hysteroscopy) are being introduced into routine clinical practice in a hurried manner without any clear evidence of benefit in most cases. These add-ons make the IVF more complicated and increase the overall cost for the treatment, which is borne by the couples and health care providers. Our current review found no high-quality evidence to support the use of these IVF add-ons in routine practice. Large, well-designed, randomized trials must be conducted to evaluate the effectiveness and safety of these interventions. There is also a pressing need to develop an evidence-dictated mechanism for introducing newer interventions into routine clinical settings.

Background Granulocyte-colony stimulating factor (G-CSF) seems to play an important role in the process of embryo implantation and continuation of pregnancy. It has been used during in vitro fertilisation (IVF) treatment for subfertile women with chronically thin endometrium and those with previous multiple IVF failures. It is currently unknown whether G-CSF is effective in improving results following assisted reproductive technology (ART). Objectives To evaluate the effectiveness and safety of G-CSF in women undergoing ART. Search methods We searched the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform in February 2019. We searched reference lists of relevant articles and handsearched relevant conference proceedings. Selection criteria Randomised controlled trials (RCTs) comparing G-CSF administration versus no treatment or placebo in subfertile women undergoing IVF treatment. Data collection and analysis Two review authors independently screened studies, extracted data, and assessed risk of bias. The primary outcomes were live-birth rate and miscarriage rate following G-CSF administration. We have reported ongoing pregnancy rate in cases where studies did not report live birth but reported ongoing pregnancy. Secondary outcomes were clinical pregnancy rate, multiple pregnancy rate, adverse events, ectopic pregnancy rate, small for gestational age at birth, abnormally adherent placenta, and congenital anomaly rate. We analysed data using risk ratio (RR), Peto odds ratio and a fixed-effect model. We assessed the quality of the evidence using the GRADE criteria. Main results We included 15 trials involving 622 women who received G-CSF and 631 women who received placebo or no additional treatment during IVF. The main limitations in the quality of the evidence were inadequate reporting of study methods and high risk of performance bias due to lack of blinding. We assessed only two of the 15 included trials as at a low risk of bias. None of the trials reported the primary effectiveness outcome of live-birth rate. We are uncertain whether G-CSF administration improves ongoing pregnancy rate compared to control in subfertile women undergoing ART (RR 1.42, 95% confidence interval (CI) 0.83 to 2.42; 2 RCTs; participants = 263; I² = 0%; very low-quality evidence). For a typical clinic with 14% ongoing pregnancy rate, G-CSF administration would be expected to result in ongoing pregnancy rates between 12% and 35%. We are uncertain whether G-CSF administration reduces miscarriage rate (Peto odds ratio 0.55, 95% CI 0.17 to 1.83; 3 RCTs; participants = 391; I² = 0%; very low-quality evidence) compared to the control group in subfertile women undergoing ART. We are uncertain whether G-CSF administration improves overall clinical pregnancy rate compared to control in subfertile women undergoing ART (RR 1.63, 95% CI 1.32 to 2.01; 14 RCTs; participants = 1253; I² = 13%; very low-quality evidence). For a typical clinic with 17% clinical pregnancy rate, G-CSF administration would be expected to result in clinical pregnancy rates between 23% and 35%. In the unselected IVF population, we are uncertain whether G-CSF administration improves clinical pregnancy rate compared to the control group (RR 1.11, 95% CI 0.77 to 1.60; 3 RCTs; participants = 404; I² = 0%; low-quality evidence). G-CSF administration may improve clinical pregnancy rate in women with two or more previous IVF failures compared to the control group (RR 2.11, 95% CI 1.56 to 2.85; 7 RCTs; participants = 643; I² = 0%; low-quality evidence). In subfertile women with thin endometrium undergoing ART, we are uncertain whether G-CSF administration improves clinical pregnancy rate compared to the control group (RR 1.58, 95% CI 0.95 to 2.63; 4 RCTs; participants = 206; I² = 30%; low-quality evidence). No study reported on multiple pregnancy rate. Only four trials reported adverse events as an outcome, and none of them reported any major adverse events following either G-CSF administration or placebo/no treatment. Authors' conclusions In subfertile women undergoing ART, we are uncertain whether the administration of G-CSF improves ongoing pregnancy or overall clinical pregnancy rates or reduces miscarriage rate compared to no treatment or placebo, whether in all women or those with thin endometrium, based on very low-quality evidence. Low-quality evidence suggests that G-CSF administration may improve clinical pregnancy rate in women with two or more IVF failures, but the included studies had unclear allocation concealment or were at high risk of performance bias.

Individualization of IVF treatment and tailored stimulation based on predicted ovarian response may maximize treatment success and minimize the risks following IVF. Whilst there has been a consensus in defining poor ovarian response and an attempt to elucidate the threshold for excessive ovarian response based on the number of oocytes retrieved following ovarian stimulation, no systematic effort has been made in order to refine the oocyte yield thresholds for a normal responder. In this opinion article we discuss the evidence behind the oocyte number thresholds for the ovarian response categories and present the rationale and merits in recognizing a new, overlooked, ovarian response group: The sub-optimal ovarian responders.

to compare the baseline characteristics and chance of live birth in the different categories of poor responders identified by the combinations of the Bologna criteria and establish whether these groups comprise a homogenous population.database containing clinical and laboratory information on IVF treatment cycles carried out at the Mother-Infant Department of the University Hospital of Modena between year 2007 and 2011 was analysed. This data was collected prospectively and recorded in the registered database of the fertility centre. Eight hundred and thirty women fulfilled the inclusion/ exclusion criteria of the study and 210 women fulfilled the Bologna criteria definition for poor ovarian response (POR). Five categories of poor responders were identified by different combinations of the Bologna criteria.There were no significant differences in female age, AFC, AMH, cycle cancellation rate and number of retrieved oocytes between the five groups. The live birth rate ranged between 5.5 and 7.4 % and was not statistically different in the five different categories of women defined as poor responders according to the Bologna criteria.The study demonstrates that the different groups of poor responders based on the Bologna criteria have similar IVF outcomes. This information validates the Bologna criteria definition as women having a uniform poor prognosis and also demonstrates that the Bologna criteria poor responders in the various subgroups represent a homogenous population with similar pre-clinical and clinical outcomes.

It is a matter of interest whether pregnancies with the use of donor sperm are associated with a higher risk of adverse perinatal outcomes compared with partner sperm. Anonymized data were obtained from the Human Fertilization & Embryology Authority. Data from 1991 to 2011 involving a total of 95,787 singleton births (4523 with donor sperm and 91,264 with partner sperm) following fresh IVF/intracytoplasmic sperm injection (ICSI) were analysed to compare perinatal outcomes of preterm birth (PTB), low birthweight (LBW) and high birthweight (HBW). The risk of LBW was significantly lower (adjusted odds ratio [aOR] 0.88, 95% confidence interval [CI]: 0.79-0.99) following donor sperm versus partner sperm IVF/ICSI. There was no significant difference in the risk of PTB (aOR 0.93, 95% CI: 0.83-1.04), early PTB (aOR 0.86, 95% CI: 0.67-1.11), very LBW (aOR 0.95, 95% CI: 0.75-1.20), HBW (aOR 1.09, 95% CI: 0.98-1.21) and very HBW (aOR 1.15, 95% CI: 0.90-1.45) following donor sperm versus partner sperm IVF/ICSI. The current study did not demonstrate an increased risk of adverse perinatal outcomes following donor sperm compared with partner sperm IVF/ICSI treatment.

The theory of a multicyclic development of follicles during the menstrual cycle prompted new approaches to ovarian stimulation, such as starting gonadotrophins for ovarian stimulation at any time during the menstrual cycle or using double stimulation during it, with stimulation in both the follicular and luteal phases. Because of the asynchrony between endometrial receptivity and embryo development with a 'non-conventional start' stimulation, all the oocytes/embryos are generally cryopreserved and transferred subsequently. This deferred transfer policy is currently possible given the advances in vitrification techniques, with success rates comparable to those following transfer with 'fresh' embryos. New stimulation approaches, together with advanced cryopreservation techniques, allow for a total 'disarticulation' between the time of the menstrual cycle, ovarian stimulation start and embryo transfer. This new approach to ovarian stimulation is particularly useful for women seeking fertility preservation, especially where a shortened time to starting cancer treatment is desirable. Also, poor responders could benefit from the new stimulation protocols by continuing ovarian stimulation after the first oocyte retrieval, thereby obtaining more oocytes or embryos compared with the conventional approach.

Anonymized data were obtained from the Human Fertilization and Embryology Authority to determine whether gestational surrogacy influences perinatal outcomes compared with pregnancies after autologous IVF. A total of 103,160 singleton live births, including 244 after gestational surrogacy, 87,571 after autologous fresh IVF and intractyoplasmic sperm injection (ICSI) and 15,345 after autologous frozen embryo transfers were analysed. Perinatal outcomes of pretern birth (PTB), low birth weight (LBW) and high birth weight (HBW) were compared. No difference was found in the risk of PTB and LBW after gestational surrogacy compared with autologous fresh IVF-ICSI: PTB (adjusted OR 0.90, 95% CI 0.56 to 1.42), LBW (adjusted OR 0.90, 95% CI 0.57 to 1.43) and gestational surrogacy compared with autologous frozen embryo transfers: PTB (adjusted OR 0.96, 95% CI 0.58 to 1.60), LBW (adjusted OR 1.16, 95% CI 0.69 to 1.96). The incidence of HBW was significantly higher after gestational surrogacy compared with fresh IVF-ICSI (adjusted OR 1.94, 95% CI 1.38 to 2.75); no difference was found in HBW between gestational surrogacy and autologous frozen embryo transfers. The dataset is limited by lack of information on confounders, i.e. ethnicity, body mass index, underlying medical history, which could result in residual confounding.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: We aim to assess the clinical effectiveness and safety profile of currently applied controlled ovarian stimulation (COS) protocols, and to generate a clinically-useful ranking of these protocols.

To perform a systematic review and meta-analysis of the known literature to assess whether the perinatal outcomes are different after oocyte donation (OD) compared to autologous oocyte (AO) in vitro fertilization (IVF) pregnancies.A systematic literature search was done for studies published in English from 1980 to 2016. Studies comparing perinatal outcomes of pregnancies following fresh or frozen OD and AO IVF were included. Meta-analysis was performed using the Rev Man 5.3 software (Cochrane Collaboration) for the perinatal outcomes of PTB (37 weeks), early PTB (32 weeks), LBW (2500g), very LBW (1500g), and SGA (10th centile). Six studies provided data on PTB, three studies on early PTB, five studies on LBW, four studies on very LBW and three studies on SGA after fresh embryo transfer. Two studies provided data on PTB, early PTB, LBW and very LBW after frozen embryo transfer.There is an increased risk of PTB following fresh embryo transfer in OD pregnancies than in AO IVF pregnancies (OR 1.45, 95% CI 1.20-1.77). If the PTB risk is assumed to be to 9% for pregnancies following AO IVF, then OD pregnancies will have a PTB risk between 10.8% and 15.9%. Similarly, the risk of LBW is higher after fresh embryo transfer in OD pregnancies than AO IVF pregnancies (OR 1.34, 95% CI 1.12-1.60). If the assumed LBW risk is 9% for AO IVF pregnancies, then OD pregnancies have a LBW risk between 10.1% and 14.4%. There is an increased risk of early PTB (OR 2.14, 95% CI 1.40-3.25) and very LBW (OR 1.51, 95% CI 1.17-1.95) in a fresh embryo transfer after OD as compared to AO IVF pregnancies.There appears to be a higher risk of adverse perinatal outcomes following fresh OD compared to AO IVF pregnancies.

Objective To compare the efficacy of the long GnRH agonist vs. the short GnRH agonist vs. the GnRH antagonist regimens in poor responders undergoing IVF. Design Randomized controlled trial. Setting Tertiary referral fertility units. Patient(s) Women with previous poor ovarian response undergoing IVF. Intervention(s) One hundred eleven women were randomized to the long GnRH agonist, short agonist, and antagonist regimens. Main Outcome Measure(s) The primary outcome was the number of oocytes retrieved. Secondary outcome measures were gonadotropin consumption, duration of stimulation, cycle cancellation rate, mature oocytes retrieved, fertilization rate, cycles reaching ET, and clinical and ongoing pregnancy rates. Result(s) Number of oocytes retrieved was significantly higher with long GnRH agonist compared with the short agonist regimen (4.42 ± 3.06 vs. 2.71 ± 1.60), while there was no significant difference between long agonist and antagonist regimens (4.42 ± 3.06 vs. 3.30 ± 2.91). Duration of stimulation and total gonadotropin dose were significantly higher with long agonist compared with short agonist and antagonist regimens. The ongoing pregnancy rate was 8.1% with long and short agonist regimens and 16.2% with the antagonist regimen. Conclusion(s) Long GnRH agonist and antagonist regimens offer a suitable choice for poor responders, whereas the short agonist regimen may be less effective because of fewer eggs retrieved.

INTRODUCTION Embryo implantation is a complex process involving maternal hormonal changes, immune responses and maturational events in the embryo. A pregnancy could fail when these events are not synchronized. It is speculated that in women, an elevation of natural killer (NK) cells may have an effect on reproductive performance, and NK cell levels in blood are currently being used as a diagnostic test to guide the initiation of therapies in patients with infertility. METHODS We conducted a systematic review to evaluate the (i) levels of NK cells in blood and endometrium in infertile versus fertile women, (ii) association between NK cells and IVF outcome, (iii) levels of NK cells in blood and endometrium in women with recurrent miscarriage (RM) versus controls. The following electronic databases were searched: Medline, EMBASE, Cochrane Library, Web of Science and National Research Register. RESULTS A total of 22 studies were included. Meta-analysis of studies that evaluated peripheral and uterine NK (uNK) cell percentages in infertile versus fertile women showed no significant difference between the two groups [standardized mean difference (SMD) -0.33; 95% confidence intervals (CI) -1.06, 0.4; P = 0.37; SMD -1.82; 95% CI -4.80, 1.17; P = 0.23 respectively]. Pooling of studies that reported peripheral NK cells as numbers showed significantly higher NK cell numbers in infertile women compared with fertile controls (SMD 3.16; 95% CI 1.07, 5.24; P = 0.003). Meta-analysis of studies that evaluated the role of NK cells in IVF outcome showed no significant difference in live birth rates in women with elevated NK cells or NK cell activity compared with women without elevated peripheral NK cells or NK cell activity (NK activity assessed using a cytotoxicity assay) (relative risk 0.57; 95% CI 0.06, 5.22; P = 0.62). Meta-analysis of studies that evaluated peripheral NK cell percentages in women with RM versus controls showed significantly higher NK cell percentages in women with RM (SMD 1.36; 95% CI 0.04, 2.69; P = 0.04). Meta-analysis of studies that evaluated peripheral NK cell numbers showed significantly higher NK cell numbers in women with RM compared with controls (SMD 0.81; 95% CI 0.47, 1.16; P < 0.00001). Meta-analysis of studies that evaluated uNK cells showed no significant difference in women with RM compared with controls (SMD 0.40; 95% CI -1.24, 2.04; P = 0.63). CONCLUSIONS Further research is needed before NK cell assessment can be recommended as a diagnostic tool in the context of female infertility or RM. There is no clear explanation as to why the results differ when data for NK cells are expressed as numbers or a percentage. On the basis of current evidence, NK cell analysis and immune therapy should be offered only in the context of clinical research.

Study question Is PGD associated with the risk of adverse perinatal outcomes such as pre-term birth (PTB) and low birth weight (LBW)? Summary answer There was no increase in the risk of adverse perinatal outcomes of PTB, and LBW following PGD compared with autologous IVF. What is known already Pregnancies resulting from ART are associated with a higher risk of pregnancy complications compared with spontaneously conceived pregnancies. The possible reason of adverse obstetric outcomes following ART has been attributed to the underlying infertility itself and embryo specific epigenetic modifications due to the IVF techniques. It is of interest whether interventions such as embryo biopsy as performed in PGD affect perinatal outcomes. Study design, size, duration Anonymous data were obtained from the Human Fertilization and Embryology Authority (HFEA), the statutory regulator of ART in the UK. The HFEA has collected data prospectively on all ART performed in the UK since 1991. Data from 1996 to 2011 involving a total of 88 010 singleton live births were analysed including 87 571 following autologous stimulated IVF ± ICSI and 439 following PGD cycles. Participants/materials, setting, methods Data on all women undergoing either a stimulated fresh IVF ± ICSI treatment cycle or a PGD cycle during the period from 1996 to 2011 were analysed to compare perinatal outcomes of PTB and LBW among singleton live births. Logistic regression analysis was performed adjusting for female age category, year of treatment, previous IVF cycles, infertility diagnosis, number of oocytes retrieved, whether IVF or ICSI was used and day of embryo transfer. Main results and the role of chance There was no increase in the risk of PTB and LBW following PGD versus autologous stimulated IVF ± ICSI treatment, unadjusted odds of PTB (odds ratio (OR) 0.68, 95% CI: 0.46-0.99) and LBW (OR 0.56, 95% CI: 0.37-0.85). After adjusting for the potential confounders, there was again no increase in the risk of the adverse perinatal outcomes following PGD: PTB (adjusted odds ratio (aOR) 0.66, 95% CI: 0.45-0.98) and LBW (aOR 0.58, 95% CI: 0.38-0.88). Limitations, reasons for caution Although the analysis was adjusted for a number of important confounders, the data set had no information on confounders such as smoking, body mass index and the medical history of women during pregnancy to allow adjustment. There was no information on the stage of embryo at biopsy, whether blastomere or trophectoderm biopsy. Wider implications for the findings The demonstration that PGD is not associated with higher risk of PTB and LBW provides reassurance towards its current expanding application. Study funding/competing interests No funding was obtained. There are no competing interests to declare.

Adenomyosis is frequent during the evaluation of infertile women. Present evidence suggests that adenomyosis has a negative impact on female fertility. Limited data from uncontrolled studies suggest that treatment of adenomyosis may improve fertility. This review critically appraises the existing evidence to determine the relationship between adenomyosis and female fertility. There is need for large epidemiological studies to substantiate the association between adenomyosis and infertility. Furthermore, if adenomyosis has a harmful impact on fertility there is a need to determine if its treatment improves fertility and the various treatment modalities reported need to be assessed for their effectiveness in randomised trials.

This systematic review and meta-analysis investigated whether gonadotrophin-releasing hormone (GnRH) antagonist protocols reduce the risk of ovarian hyperstimulation syndrome (OHSS) in women with polycystic ovary syndrome undergoing IVF compared with the long agonist protocol. Searches were conducted on MEDLINE, EMBASE, Cochrane Library, National Research Register and ISI Conference Proceedings. Primary outcome was OHSS incidence. Secondary outcomes were total duration and dose of gonadotrophin, number of oocytes retrieved and clinical pregnancy and miscarriage rates. A total of 966 women were included in nine randomized controlled trials. There was inconsistency in definition, classification of severity and reporting of the OHSS rate. There was no difference in the incidence of severe OHSS in the antagonist group compared with the long agonist group (relative risk 0.61; 95% CI 0.23 to 1.64). However, when all moderate and severe OHSS cases were pooled, the antagonist protocol was associated with significantly lower risk of OHSS (relative risk 0.60; 95% CI 0.48-0.76; P

As the use of routine assisted reproductive technology (ART) becomes widespread along with the extended applications such as ART with donor gametes, surrogacy, and preimplantation genetic testing (PGT), it becomes more pertinent to evaluate risks associated with them. Perinatal outcomes and long-term safety for the women and children are paramount. In this review, we aimed to detail the perinatal outcomes in relation to the ART procedures routinely applied as the extended applications of ART with a focus on singleton pregnancies. While there seems to be a higher risk of adverse perinatal outcomes with some of the ART procedures, the absolute risk increase is generally low. It is important for clinicians to have this knowledge to better counsel and care for their patients.

background: There are conflicting results on whether the rate of blastocyst development before freezing influences the outcome of frozen-thawed blastocyst transfers. methods: We conducted a systematic review and meta-analysis of controlled studies to compare pregnancy outcomes following transfer of thawed blastocysts that were frozen either on Day 5 or Day 6 following fertilization in vitro. Searches were conducted on MEDLINE, EMBASE, Cochrane Library and Web of Science. Study selection and data extraction were conducted independently by two reviewers. The Newcastle-Ottawa Quality Assessment Scale was used for quality assessment. results: We identified 15 controlled studies comprising 2502 frozen-thawed transfers involving blastocysts that were either frozen on Day 5 or Day 6. Meta-analysis of these studies showed significantly higher clinical pregnancy rate [relative risk (RR) ¼ 1.14, 95% confidence interval (CI): 1.03 –1.26, P ¼ 0.01] and ongoing pregnancy/live birth rate (RR ¼ 1.15, 95% CI: 1.01– 1.30, P ¼ 0.03) with Day 5 compared with Day 6 frozen-thawed blastocyst transfers. Sensitivity analysis of those studies where blastocysts frozen on Day 5 or Day 6 were at the same stage of development showed no significant difference in the clinical pregnancy rate (RR ¼ 1.07, 95% CI: 0.87 –1.33, P ¼ 0.51) and ongoing pregnancy/live birth rate (RR ¼ 1.08, 95% CI: 0.92 –1.27, P ¼ 0.36). conclusion: Slower developing blastocysts cryopreserved on Day 6 but at the same stage of development as those developing to the blastocyst stage on Day 5 have similar clinical pregnancy and ongoing pregnancy/live birth rates following frozen-thawed blastocyst transfers.

Background Numerous randomised studies have reported pregnancy outcome in women who received acupuncture during their in vitro fertilisation (IVF) treatment cycle. Objective The objective of this study was to conduct a systematic review with meta-analysis of the trials of acupuncture during IVF treatment on the outcomes of clinical pregnancy and live birth rates. Search strategy Searches were conducted in MEDLINE, EMBASE, Cochrane Library, ISI Proceedings and SCISEARCH. Selection criteria All randomised controlled trials that evaluated the effects of acupuncture compared with no treatment or sham acupuncture in women undergoing IVF–intracytoplasmic sperm injection treatment were included. Data collection and analysis Study selection, quality appraisal and data extraction were performed independently and in duplicate. A sensitivity analysis was conducted where the meta-analysis was restricted to trials in which sham acupuncture was used in the control group. Meta-regression analysis was used to explore the association between study characteristics and pregnancy rates. Main results Thirteen relevant trials, including a total of 2500 women randomised to either acupuncture or control group, were identified. No evidence of publication bias was found (Begg’s test, P = 0.50). Five trials (n = 877) evaluated IVF outcome when acupuncture was performed around the time of transvaginal oocyte retrieval, while eight trials (n = 1623) reported IVF outcome when acupuncture was performed around the time of embryo transfer (ET). Meta-analysis of the five studies of acupuncture around the time of egg collection did not show a significant difference in clinical pregnancy (relative risks [RR] = 1.06, 95% CI 0.82–1.37, P = 0.65). Meta-analysis of the eight studies of acupuncture around the time of ET showed no difference in the clinical pregnancy rate (RR = 1.23, 95% CI 0.96–1.58, P = 0.1). Live birth data were available from five of the eight studies of acupuncture around the time of ET. Meta-analysis of these studies did not show a significant increase in live birth rate with acupuncture (RR = 1.34, 95% CI 0.85–2.11). Using meta-regression, no significant association between any of the studied covariates and clinical pregnancy rate was found (P > 0.05 for all covariates). Conclusion Currently available literature does not provide sufficient evidence that adjuvant acupuncture improves IVF clinical pregnancy rate.

A systematic review of studies evaluating the influence of outpatient (office) hysteroscopy on the outcome of the subsequent IVF cycle was conducted. MEDLINE, EMBASE, the Cochrane Library, National Research Register, ISI Conference Proceedings, ISRCTN Register and Meta-register were searched for randomized controlled trials (up to July 2007). All trials comparing the outcome of IVF treatment performed in patients who had outpatient hysteroscopy in the cycle preceding their IVF treatment with a control group in which hysteroscopy was not performed were included. Study selection, quality appraisal and data extraction were performed independently and in duplicate. Study authors were contacted for additional information. The main outcome measure was pregnancy rate. In total, 1691 participants were included in two randomized (n = 941) and three non-randomized controlled studies (n = 750). The quality of the studies was variable. Meta-analyses of the results of five studies showed evidence of benefit from outpatient hysteroscopy in improving the pregnancy rate in the subsequent IVF cycle (pooled relative risk = 1.75, 95% CI 1.51-2.03). The evidence from randomized trials was consistent with that from non-randomized controlled studies. Future robust randomized trials comparing outpatient hysteroscopy or mini-hysteroscopy with no intervention before IVF treatment would be a useful addition to further guide clinical practice.